The present invention relates to a process for the chromatographic separation of mixtures of diastereomers comprising RSS— and SSS—N-α[1-carboxy-3-phenylpropyl]lysylproline (Lisinopril®; also denoted LP below).
Lisinopril® is an ACE inhibitor and is licensed as an antihypertensive.
When this peptide derivative is synthesized from two chiral amino acids, a new chiral center is formed (J. Org. Chem. 1988, 53, 836 et seq.). However, the reaction used does not proceed completely selectively with regard to this center. As a consequence, two diastereomers are inevitably formed, only one of which constitutes the actual active substance.
U.S. Pat. No. 4,472,380 and U.S. Pat. No. 4,374,829 describe the separation of the diastereomers thereof by adsorption chromatography on XAD-2 phases. The eluent used is a mixture comprising an aqueous ammonia solution and an organic solvent, such as for example methanol or acetonitrile.
The disadvantages of this chromatographic process are firstly that, when purifying the reaction solution from an LP production process, this operation is dependent upon the presence of organic solvents in the eluent as the compounds to be separated would otherwise either not be eluted from the stationary phases or would be eluted in an inadequately purified form. Residues of all kinds in the actual active substance and in particular these organic solvents are, however, highly undesirable, especially in the pharmaceuticals sector, as they could give rise to side effects or even be toxic. Reference may be made in this connection to the necessity of complying with the specification of the active substance required by government regulations.
Furthermore, addition of the organic solvents is a cost factor in the industrial production process with regard to use and recycling. Moreover, the stated adsorption chromatography columns have poor loadability for this separation task, meaning that throughput, viewed on an industrial scale, leaves something to be desired.
Accordingly, it is an object of the invention to separate the diastereomers of RSS— and SSS—N-α[1-carboxy-3-phenylpropyl]lysylproline, without encountering the disadvantages of the prior art chromatographic processes, which may in particular be performed without addition of organic solvents during separation, in particular during purification of the reaction solution from an LP production process, and which permits the stationary phase to be extremely highly loaded with the mixture of substances to be purified.